Heterocycles useful as modulators of ion channels

ABSTRACT

The present invention relates to compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119 of U.S.Provisional application Ser. No. 60/685,971 filed May 31, 2005, theentire contents of which is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ionchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain(ee, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels andpain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R.Cummins, et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v)1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See, Noda, M., H. Suzuki, et al. (1989) “A single pointmutation confers tetrodotoxin and saxitoxin insensitivity on the sodiumchannel II” FEBS Lett 259(1): 213-6).

TABLE 1 (Abbreviations: CNS = central nervous system, PNS = peripheralnervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Naisoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain,Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nMNeurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic,injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μMArrhythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread,most abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminalsdisorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG &TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to beuseful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (ee, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (ee Lai, J., M. S. Gold,et al. (2002) “Inhibition of neuropathic pain by decreased expression ofthe tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52,and Lai, J., J. C. Hunter, et al. (2000) “Blockade of neuropathic painby antisense targeting of tetrodotoxin-resistant sodium channels insensory neurons” Methods Enzymol 314: 201-13). NaV1.8 protein isupregulated along uninjured C-fibers adjacent to the nerve injury.Antisense treatment prevents the redistribution of NaV1.8 along thenerve and reverses neuropathic pain. Taken together the gene-knockoutand antisense data support a role for NaV1.8 in the detection andtransmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell,et al. (1999) “Plasticity of sodium channel expression in DRG neurons inthe chronic constriction injury model of neuropathic pain.” Pain 83(3):591-600.) The timecourse of the increase in NaV1.3 parallels theappearance of allodynia in animal models subsequent to nerve injury. Thebiophysics of the NaV1.3 channel is distinctive in that it shows veryfast repriming after inactivation following an action potential. Thisallows for sustained rates of high firing as is often seen in theinjured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3sodium channels: rapid repriming and slow closed-state inactivationdisplay quantitative differences after expression in a mammalian cellline and in spinal sensory neurons” J Neurosci 21(16): 5952-61). NaV1.3is expressed in the central and peripheral systems of man. NaV1.9 issimilar to NaV1.8 as it is selectively localized to small sensoryneurons of the dorsal root ganglion and trigeminal ganglion (See, Fang,X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22(17): 7425-33). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25(5): 253-9). These twobiophysical properties allow NaV1.9 to play a role in establishing theresting membrane potential of nociceptive neurons. The resting membranepotential of NaV1.9 expressing cells is in the −55 to −50 mV rangecompared to −65 mV for most other peripheral and central neurons. Thispersistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli. In chronic pain states, nerve and nerveending can become swollen and hypersensitive exhibiting high frequencyaction potential firing with mild or even no stimulation. Thesepathologic nerve swellings are termed neuromas and the primary Nachannels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T.,L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channelsin painful human neuroma-evidence from immunocytochemistry” ActaNeurochir (Wien) 144(8): 803-10; discussion 810). NaV1.6 and NaV1.7 arealso expressed in dorsal root ganglion neurons and contribute to thesmall TTX sensitive component seen in these cells. NaV1.7 in particularmy therefore be a potential pain target in addition to it's role inneuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al.(1995) “Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na⁺ channel alphaII subunit gene Na(v)1.2 in a patient with febrile and afebrile seizurescauses channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) havebeen linked to epilepsy conditions including febrile seizures. There areover 9 genetic mutations in NaV1.1 associated with febrile seizures(See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations ofvoltage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na⁺ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (ee Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na⁺channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); neuroprotection (ee Taylor, C. P. and L. S,Narasimhan (1997) “Sodium channels and therapy of central nervous systemdiseases” Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz,G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of localanaesthetics unveil the potential role of sodium channels in neuropathicpain.” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed forthe study of sodium channel modulators for numerous different painindications. E.g., malignant chronic pain, see, Kohase, H., et al., ActaAnaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase,H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignantchronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994;42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav BrainRes. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al.,Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y.et al., J Neurosci Methods. 2001; 104(2):191-8); Neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9; neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial painsyndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002;16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46);fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995;15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain ResMol Brain Res. 1999; 67(1):87-97); chronic visceral pain, including,abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000;119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., NeurosciLett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., etal., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N.,et al., Pain. 2003; 105(1-2):223-30; La J H et al., World Gastroenterol.2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark,Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al.,J Neurophysiol. 1999; 81(2):479-93); tension headache, including,cluster headaches (see, Costa, A., et al., Cephalalgia. 2000;20(2):85-91); chronic neuropathic pain, including, post-herpeticneuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim &Chung 1992, Pain 50:355); diabetic neuropathy (see, Beidoun A et al.,Clin J Pain. 2004; 20(3):174-8; Courteix, C., et al., Pain. 1993;53(1):81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, NedTijdschr Geneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004;107(1-2):147-58; Oh, S. B., et al., J. Neurosci. 2001; 21(14):5027-35);trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med OralPathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp BrainRes. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda,M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensoryneuropathies (see, Lee, M. J., et al., Hum Mol. Genet. 2003;12(15):1917-25); peripheral nerve injury (see, Attal, N., et al.,Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett &Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149;Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas(see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor &Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal anddistal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27);radiculopathy (see, Devers & Galer, (see, Clin J Pain. 2000;16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapyinduced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996;73(1):259-65); radiotherapy-induced neuropathic pain; post-mastectomypain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain(Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cordinjury pain (see, Hains, B. C., et al., Exp Neurol. 2000;164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., etal., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome(see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; XantosD et al., J Pain. 2004; 5(3 Suppl 2):S1); phanton pain (see, Weber, W.E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain.1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can JAnaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see,Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J.,et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; jointpain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22);mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000;85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay,M., et al., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain,including, abdominal pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; etc (see, Giambernardino, M. A., etal., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain(see, Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvicpain, renal colic pain, acute obstetric pain, including, labor pain(see, Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesareansection pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, including, endometriosis (see, Cason, A. M., et al.,Horm Behav. 2003; 44(2):123-31); acute herpes zoster pain; sickle cellanemia; acute pancreatitis (see, Toma, H; Gastroenterology. 2000;119(5):1373-81); breakthrough pain; orofacial pain, including, sinusitispain, dental pain (see, Nusstein, J., et al., J Endod. 1998;24(7):487-91; Chidiac, J. J., et al., Eur J Pain. 2002; 6(1):55-67);multiple sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci.1999; 162(2):162-8; Waxman, Stephen G. et al, PNAS 2000; 97(21):11598-602); pain in depression (see, Greene B, Curr Med Res Opin. 2003;19(4):272-7); leprosy pain; behcet's disease pain; adiposis dolorosa(see, Devillers & Oranje, Clin Exp Dermatol. 1999; 24(3):240-1);phlebitic pain; Guillain-Barre pain; painful legs and moving toes;Haglund syndrome; erythromelalgia pain (see, Legroux-Crespel, E., etal., Ann Dermatol Venereol. 2003; 130(4):429-33); Fabry's disease pain(see, Germain, D. P., J Soc Biol. 2002; 196(2):183-90); Bladder andurogenital disease, including, urinary incontinence (see, Berggren, T.,et al., J Urol. 1993; 150(5 Pt 1):1540-3); hyperactivity bladder (see,Chuang, Y. C., et al., Urology. 2003; 61(3):664-70); painful bladdersyndrome (see, Yoshimura, N., et al., J. Neurosci. 2001; 21(21):8690-6);interstitial cyctitis (IC) (see, Giannakopoulos & Campilomatos, ArchItal Urol Nefrol Androl. 1992; 64(4):337-9; Boucher, M., et al., J Urol.2000; 164(1):203-8); and prostatitis (see, Mayersak, J. S., Int Surg.1998; 83(4):347-9; Keith, I. M., et al., J Urol. 2001; 166(1):323-8).

Voltage-gated calcium channels are membrane-spanning, multi-subunitproteins that open in response to membrane depolarization, allowing Caentry from the extracellular milieu. Calcium channels were initiallyclassified based on the time and voltage-dependence of channel openingand on the sensitivity to pharmacological block. The categories werelow-voltage activated (primarily T-type) and high-voltage activated (L,N, P, Q or R-type). This classification scheme was replaced by anomenclature based upon the molecular subunit composition, as summarizedin Table B (Hockerman G H, Peterson B Z, Johnson B D, Catterall W A.1997. Annu Rev Pharmacol Toxicol 37: 361-96; Striessnig J. 1999. CellPhysiol Biochem 9: 242-69). There are four primary subunit types thatmake up calcium channels—α₁, α₂δ, β and γ (See, e.g., De Waard et al.Structural and functional diversity of voltage-activated calciumchannels. In Ion Channels, (ed. T. Narahashi) 41-87, (Plenum Press, NewYork, 1996)). The α₁ subunit is the primary determinant of thepharmacological properties and contains the channel pore and voltagesensor (Hockerman et al., 1997; Striessnig, 1999). Ten isoforms of theα₁ subunit are known, as indicated in Table I below. The α₂δ subunitconsists of two disulfide linked subunits, α₂, which is primarilyextracellular and a transmembrane δ subunit. Four isoforms of α₂δ areknown, α₂δ-1, α₂δ-2, α₂δ-3 and α₂δ-4. The β subunit is anon-glycosylated cytoplasmic protein that binds to the α₁ subunit. Fourisoforms are known, termed β₁ to β₄. The γ subunit is a transmembraneprotein that has been biochemically isolated as a component of Ca_(v)1and Ca_(v)2 channels. At least 8 isoforms are known (γ₁ to γ₈) [Kang MG, Campbell K P. 2003. J Biol Chem 278: 21315-8]. The nomenclature forvoltage-gated calcium channels is based upon the content of the α₁subunit, as indicated in Table I. Each type of α₁ subunit can associatewith a variety of β, α₂δ or γ subunits, so that each Ca_(v) typecorresponds to many different combinations of subunits.

TABLE B Cav Nomenclature α₁ subunit Pharmacological name Ca_(v)1.1α_(1S) L-type Ca_(v)1.2 α_(1C) L-type Ca_(v)1.3 α_(1D) L-type Ca_(v)1.4α_(1F) Ca_(v)2.1 α_(1A) P- or Q-type Ca_(v)2.2 α_(1B) N-type Ca_(v)2.3α_(1E) R-type Ca_(v)3.1 α_(1G) T-type Ca_(v)3.2 α_(1H) T-type Ca_(v)3.3α_(1I) T-type

Ca_(v)2 currents are found almost exclusively in the central andperipheral nervous system and in neuroendocrine cells and constitute thepredominant forms of presynaptic voltage-gated calcium current.Presynaptic action potentials cause channel opening and neurotransmitterrelease is steeply dependent upon the subsequent calcium entry. Thus,Ca_(v)2 channels play a central role in mediating neurotransmitterrelease.

Ca_(v)2.1 and Ca_(v)2.2 contain high affinity binding sites for thepeptide toxins ω-conotoxin-MVIIC and ω-conotoxin-GVIA, respectively, andthese peptides have been used to determine the distribution and functionof each channel type. Ca_(v)2.2 is highly expressed at the presynapticnerve terminals of neurons from the dorsal root ganglion and neurons oflamina I and II of the dorsal horn (Westenbroek R E, Hoskins L,Catterall W A. 1998. J Neurosci 18: 6319-30; Cizkova D, Marsala J,Lukacova N, Marsala M, Jergova S, et al. 2002. Exp Brain Res 147:456-63). Ca_(v)2.2 channels are also found in presynaptic terminalsbetween second and third order interneurons in the spinal cord. Bothsites of neurotransmission are very important in relaying paininformation to the brain.

Pain can be roughly divided into three different types: acute,inflammatory, and neuropathic. Acute pain serves an important protectivefunction in keeping the organism safe from stimuli that may producetissue damage. Severe thermal, mechanical, or chemical inputs have thepotential to cause severe damage to the organism if unheeded. Acute painserves to quickly remove the individual from the damaging environment.Acute pain by its very nature generally is short lasting and intense.Inflammatory pain on the other had may last for much longer periods oftime and it's intensity is more graded. Inflammation may occur for manyreasons including tissue damage, autoimmune response, and pathogeninvasion. Inflammatory pain is mediated by an “inflammatory soup” thatconsists of substance P, histamines, acid, prostaglandin, bradykinin,CGRP, cytokines, ATP, and neurotransmitter release. The third class ofpain is neuropathic and involves nerve damage that results inreorganization of neuronal proteins and circuits yielding a pathologic“sensitized” state that can produce chronic pain lasting for years. Thistype of pain provides no adaptive benefit and is particularly difficultto treat with existing therapies.

Pain, particularly neuropathic and intractable pain is a large unmetmedical need. Millions of individuals suffer from severe pain that isnot well controlled by current therapeutics. The current drugs used totreat pain include NSAIDS, COX2 inhibitors, opioids, tricyclicantidepressants, and anticonvulsants. Neuropathic pain has beenparticularly difficult to treat as it does not respond well to opioidsuntil high doses are reached. Gabapentin is currently the favoredtherapeutic for the treatment of neuropathic pain although it works inonly 60% of patients where it shows modest efficacy. The drug is howeververy safe and side effects are generally tolerable although sedation isan issue at higher doses.

Validation of Cav2.2 as a target for the treatment of neuropathic painis provided by studies with ziconotide (also known asω-conotoxin-MVIIA), a selective peptide blocker of this channel(Bowersox S S, Gadbois T, Singh T, Pettus M, Wang Y X, Luther R R. 1996.J Pharmacol Exp Ther 279: 1243-9; Jain K K. 2000. Exp. Opin. Invest.Drugs 9: 2403-10; Vanegas H, Schaible H.2000. Pain 85: 9-18). In man,intrathecal infusion of Ziconotide is effective for the treatment ofintractable pain, cancer pain, opioid resistant pain, and neuropathicpain. The toxin has an 85% success rate for the treatment of pain inhumans with a greater potency than morphine. An orally availableantagonist of Ca_(v)2.2 should have similar efficacy without the needfor intrathecal infusion. Ca_(v)2.1 and Ca_(v)2.3 are also in neurons ofnociceptive pathways and antagonists of these channels could be used totreat pain.

Antagonists of Ca_(v)2.1, Ca_(v)2.2 or Ca_(v)2.3 should also be usefulfor treating other pathologies of the central nervous system thatapparently involve excessive calcium entry. Cerebral ischaemia andstroke are associated with excessive calcium entry due to depolarizationof neurons. The Ca_(v)2.2 antagonist ziconotide is effective in reducinginfarct size in a focal ischemia model using laboratory animals,suggesting that Ca_(v)2.2 antagonists could be used for the treatment ofstroke. Likewise, reducing excessive calcium influx into neurons may beuseful for the treatment of epilepsy, traumatic brain injury,Alzheimer's disease, multi-infarct dementia and other classes ofdementia, amyotrophic lateral sclerosis, amnesia, or neuronal damagecaused by poison or other toxic substances.

Ca_(v)2.2 also mediates release of neurotransmitters from neurons of thesympathetic nervous system and antagonists could be used to treatcardiovascular diseases such as hypertension, cardiac arrhythmia, anginapectoris, myocardial infarction, and congestive heart failure.

Unfortunately, as described above, the efficacy of currently used sodiumchannel blockers and calcium channel blockers for the disease statesdescribed above has been to a large extent limited by a number of sideeffects. These side effects include various CNS disturbances such asblurred vision, dizziness, nausea, and sedation as well more potentiallylife threatening cardiac arrhythmias and cardiac failure. Accordingly,there remains a need to develop additional Na channel and Ca channelantagonists, preferably those with higher potency and fewer sideeffects. Unfortunately, as described above, the efficacy of currentlyused sodium channel blockers and calcium channel blockers for thedisease states described above has been to a large extent limited by anumber of side effects. These side effects include various CNSdisturbances such as blurred vision, dizziness, nausea, and sedation aswell more potentially life threatening cardiac arrhythmias and cardiacfailure. Accordingly, there remains a need to develop additional Nachannel and Ca channel antagonists, preferably those with higher potencyand fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels and/or calcium channels.These are compounds of formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

I. General Description of Compounds of the Invention:

In one embodiment, the present invention provides compounds of formulaI:

or a pharmaceutically acceptable salt thereof,wherein:

is a single or double bond;

X₁ and X₂ each is independently ═CR³—, ═N—, —O—, —S—, or —NR³—;

X₃ is R³ or a lone pair of electrons;

provided that X₁, X₂, and N(X₃), taken together with the interveningcarbon atoms form a 5-membered heteroaryl ring;

W is halo, OR′, SR′, N(R′)₂, NRC(O)R′, S(O)₂N(R′)₂, OC(O)R′,OC(O)N(R′)₂, NR(S(O)₂R′, OP(O)(OR′)₂, OP(O)₂OR′, OP(O)(R′)₂, CHF₂, CH₂F,or CF₃;

R¹ and R², taken together with the nitrogen atom, form a 3-12-memberedmonocyclic or bicyclic saturated, partially unsaturated, or fullyunsaturated ring having 0-3 additional heteroatoms independentlyselected from nitrogen, sulfur, or oxygen, wherein said ring isoptionally substituted at one or more substitutable ring atoms with zindependent occurrences of —R⁴, wherein z is 0-5;

y is 0-5;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(x); wherein Q isa bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx isindependently selected from —R′, halogen, —NO₂, —CN, —OR′, —SR′,—N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group;

each occurrence of R′ is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, the following compounds are excluded:

(i) when X₁ is S, X₂ is ═CH—, X³ is a lone pair of electrons, W,together with R⁵ and y is 2,4-difluorophenyl, then R¹ and R² takentogether is not optionally substituted2,3-dihydro-1H-isoindol-1-one-2-yl;

(ii) when X₁ is S, X₂ is ═CH—, X³ is a lone pair of electrons, W,together with R⁵ and y is 2,4-dichlorophenyl, then R¹ and R² takentogether is not optionally substituted 2,3-dihydro-1H-indol-1-yl or anoptionally substituted tetracyclic ring system;

(iii) when X₁ is S, X₂ is ═CMe-, X³ is a lone pair of electrons, W,together with R⁵ and y is 2,4-dimethoxyphenyl, then R¹ and R² takentogether is not an optionally substituted pyrrol-1-yl ring fused to anoptionally substituted pyridazine ring;

(iv) when X₁ is S, X₂ is ═CR³—, and X³ is a lone pair of electrons, thenR¹ and R² taken together is not an optionally substituted pyrrol-1-yl;

(v) when X₁ is ═N—, X² is O, X³ is a lone pair of electrons, and W ishalo, then R¹ and R² taken together is not1,4-diazabicyclo[3.2.2]nonan-1-yl;

(vi) when X₁ is S, X₂ is ═CH—, X³ is a lone pair of electrons, W,together with R⁵ and y is 2-chlorophenyl, then R¹ and R² taken togetheris not an optionally substituted imidazol-1-yl;

(vii) when X₁ is ═N—, X₂ is ═CH—, X₃ is H, y is 0, and W is NHSO₂Ar′,wherein Ar′ is an optionally substituted phenyl, then R¹ and R² takentogether is not 2-butanamido-pyrrolidin-1-yl;

(viii) when X₁ is ═N—, X₂ is ═CH— or ═C(Cl)—, X₃ is H, and W isNHSO₂Ar′, wherein Ar′ is an optionally substituted phenyl or NHC(O)R,wherein R is an optionally substituted aliphatic, then R¹ and R² takentogether is not 3-[(dimethylamino)sulfonyl]amino-morpholin-4-yl or2-(methoxycarbonyl)amino-4,5-dichloro-1H-imidazol-1-yl;

(ix) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, W is OHor OMe, then R¹ and R² taken together is not3,4-dihydro-2-(1H)-quinozolin-3-one-2-yl;

(x) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, and W ishalo or OR′, then R¹ and R² taken together is not an optionallysubstituted 2-imino-thiazolidin-4-one-3-yl;

(xi) when X₁ is S, X₂ is ═CH—, and X₃ is a lone pair of electrons, thenR¹ and R² taken together is not an optionally substitutedazetidin-2-one-1-yl;

(xii) when X₁ is S, X₂ is ═CR³—, X₃ is a lone pair of electrons, and Wis OH or halo, then R¹ and R² taken together is not an optionallysubstituted 3,4-dihydro-(3H)-quinazolin-4-one-3-yl;

(xiii) when X₁ is S, X₂ is ═CR³—, X₃ is a lone pair of electrons, and Wis halo, OMe, or NHSO₂Ar′, wherein Ar′ is an optionally substitutedphenyl, then R¹ and R² taken together is not an optionally substitutedring selected from thiazolidin-4-one-3-yl, 2,4-dioxo-imidazolin-1-yl,4,5-dihydro-5-oxo-(1H)-imidazol-1-yl, or azetidin-1-yl;

(xiv) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, and W ishalo, then R¹ and R² taken together is not1,2,3,4-tetrahydro-(1H)-quinazolin-2,4-dioxo-3-yl; and

(xv) when X₁ is ═N—, X₂ is ═CR³—, X₃ is H, then R¹ and R² taken togetheris not 3,5-dioxo-1,2,4-triazolidin-4-yl, 2,5-dioxo-pyrrolidin-1-yl, or2,5-dioxo-imidazolidin-1-yl.

2. Compounds and Definitions:

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule. Insome embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”)refers to a monocyclic or bicyclic hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic, that has a single point of attachment to the rest ofthe molecule wherein any individual ring in said bicyclic ring systemhas 3-7 members. Suitable aliphatic groups include, but are not limitedto, linear or branched, substituted or unsubstituted alkyl, alkenyl,alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise specified herein, suitable substituentson the unsaturated carbon atom of an aryl or heteroaryl group aregenerally selected from halogen; —R^(o); —OR^(o); —SR^(o); phenyl (Ph)optionally substituted with R^(o); —O(Ph) optionally substituted withR^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph),optionally substituted with R^(o); —NO₂; —CN; —N(R^(o))₂;—NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂;—C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o);—C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂;—(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionally substituted with R^(o);—O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionallysubstituted with R^(o); or —CH═CH(Ph), optionally substituted withR^(o); wherein each independent occurrence of R^(o) is selected fromhydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5-6membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph),or, notwithstanding the definition above, two independent occurrences ofR^(o), on the same substituent or different substituents, taken togetherwith the atom(s) to which each R^(o) group is bound, to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Unless otherwise specified herein, optional substituents on thealiphatic group of R^(o) are selected from NH₂, NH(C₁₋₄aliphatic),N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂,CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), orhaloC₁₋₄aliphatic, wherein each of the foregoing C₁₋₄aliphatic groups ofR^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise specified herein, suitable substituentson the saturated carbon of an aliphatic or heteroaliphatic group, or ofa non-aromatic heterocyclic ring are selected from those listed abovefor the unsaturated carbon of an aryl or heteroaryl group andadditionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group.

Unless otherwise specified herein, optional substituents on the nitrogenof a non-aromatic heterocyclic ring are generally selected from —R⁺,—N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺,—SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ ishydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R⁺, on the same substituent ordifferent substituents, taken together with the atom(s) to which each R⁺group is bound, form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

Unless otherwise specified herein, optional substituents on thealiphatic group or the phenyl ring of R⁺ are selected from —NH₂,—NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH,—O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoingCl₄aliphatic groups of R⁺ is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which they are bound to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which each variable is bound include,but are not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein) thatare bound to the same atom and are taken together with that atom to forma ring, for example, N(R^(o))₂, where both occurrences of R^(o) aretaken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, R, R′ or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise specified herein, structures depicted herein are alsomeant to include all isomeric (e.g., enantiomeric, diastereomeric, andgeometric (or conformational)) forms of the structure; for example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon or a nitrogen by a ¹⁵N nitrogen are withinthe scope of this invention. Such compounds are useful, for example, asanalytical tools or probes in biological assays.

3. Description of Exemplary Compounds:

In one embodiment, X₁, X₂, and X₃ taken together form a ring selectedfrom:

In one embodiment, X₁, X₂, and X₃ taken together form ring i. Or, saidring is ring ii. Or, said ring is ring iii.

In another embodiment, X₁, X₂, and X₃ taken together form a ringselected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring iv. Or, saidring is ring v. Or, said ring is ring vi.

In another embodiment, X₁, X₂, and X₃ taken together form a ringselected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring vii. Or, saidring is ring viii. Or, said ring is ring ix.

In another embodiment, X₁, X₂, and X₃ taken together form a ringselected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring x. Or, saidring is ring xi. Or, said ring is ring xii.

In another embodiment X₁, X₂, and X₃ taken together form ring xiii:

In one embodiment, X₁, X₂, and X₃ are taken together to form ring ii, Wis halo or OR′, R¹ and R², taken together with the nitrogen atom, form a6-membered monocyclic saturated ring having 0-1 additional heteroatomsselected from nitrogen, wherein said ring is optionally substituted atone or more substitutable ring atoms with z independent occurrences of—R⁴, wherein z is 0.

In another embodiment, X₁, X₂, and X₃ are taken together to form ringii, W is halo or OR′, and R¹ and R² taken together, form ring mm or nn.

In another embodiment, X₁, X₂, and X₃ are taken together to form ringii, W is halo or OR′, and R¹ and R² form a ring shown below:

In another embodiment, X₁, X₂, and X₃ are taken together to form ringviii or xi, W is halo or OR′, R¹ and R², taken together with thenitrogen atom, form a 6-membered monocyclic saturated ring having 0-1additional heteroatoms selected from nitrogen, wherein said ring isoptionally substituted at one or more substitutable ring atoms with zindependent occurrences of —R⁴, wherein z is 0.

In another embodiment, X₁, X₂, and X₃ are taken together to form viii orxi, W is halo or OR′, and R¹ and R² taken together, form ring mm or nn.

In one embodiment, R¹ and R², taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-8-memberedmonocyclic, saturated or partially unsaturated ring having 0-3additional heteroatoms independently selected from nitrogen, sulfur, oroxygen; wherein the ring formed by R¹ and R² taken together, are eachoptionally and independently substituted at one or more substitutablecarbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴,wherein z is 0-5.

In another embodiment, R¹ and R², taken together with the nitrogen atomto which they are bound, form an optionally substituted 3-8-memberedmonocyclic, saturated or partially unsaturated ring having 0-3additional heteroatoms independently selected from nitrogen, sulfur, oroxygen, wherein the ring atom in each of R¹ and R² adjacent to saidnitrogen atom is a —CH₂—; wherein the ring formed by R¹ and R² takentogether, are each optionally and independently substituted at one ormore substitutable carbon, nitrogen, or sulfur atoms with z independentoccurrences of —R⁴, wherein z is 0-5.

In one embodiment of the present invention, R¹ and R² taken togetherform an azetidinyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform a pyrrolidinyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform a piperidinyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform a piperazinyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform a morpholinyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform a thiomorpholinyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform an azepanyl ring:

In another embodiment of the present invention, R¹ and R² taken togetherform an azocanyl ring:

In one embodiment, R¹ and R² together form a ring (ii) or (jj) as shownbelow:

wherein:

G₁ is —N—, —CH—NH—, or —CH—CH₂—NH—;

each of m₁ and n₁ is independently 0-3, provided that m₁+n₁ is 2-6;p₁ is 0-2;z is 0-4;each R^(XX) is hydrogen, C₁₋₆ aliphatic group, a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein R^(XX) is optionally substitutedwith w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3;provided that both R^(XX) are not simultaneously hydrogen;

R^(YY) is hydrogen, —COR′, —CO₂R′, —CON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or —PO(R′);

each occurrence of R¹¹ is independently Q-R^(X); wherein Q is a bond oris a C₁-C₆ alkylidene chain wherein up to two non-adjacent methyleneunits of Q are optionally and independently replaced by —NR—, —S—, —O—,—CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—,—NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—,—PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx isindependently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic grouphaving up to three substituents; and each occurrence of R′ isindependently hydrogen or C₁₋₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ has up to foursubstituents; or R and R′, two occurrences of R, or two occurrences ofR′, are taken together with the atom(s) to which they are bound to forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment of the present invention, one R^(XX) is hydrogen andthe other R^(XX) is not hydrogen.

In another embodiment of the present invention, both R^(XX) are nothydrogen.

In one embodiment of the present invention, p₁ is 0. Or, p₁ is 1. Or, p₁is 2.

In one embodiment of the present invention, m₁ and n₁ each is 1. Or, mland n₁ each is 2. Or, m₁ and n₁ each is 3.

In one embodiment of the present invention, R^(XX) is C₁₋₆ aliphaticgroup, wherein R^(XX) is optionally substituted with w₁ independentoccurrences of —R¹¹, wherein w₁ is 0-3. Or, Rx is C₁-C₆ alkyl groupoptionally substituted with w₁ independent occurrences of —R¹¹, whereinw₁ is 0-3.

In one embodiment of the present invention, R^(XX) is C₁-C₆ alkyl group.

In another embodiment of the present invention, R^(XX) is a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R^(XX) is optionallysubstituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3.

In another embodiment, R^(XX) is a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R^(XX)is optionally substituted with w₁ independent occurrences of —R¹¹,wherein w₁ is 0-3.

In another embodiment, R^(XX) is an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein R^(XX) is optionally substituted with w₁ independent occurrencesof —R¹¹, wherein w₁ is 0-3.

In another embodiment, R^(YY) is hydrogen, —COR′, —CO₂R′, —CON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′,or —PO(R′).

Or, R^(YY) is hydrogen.

In another embodiment, R^(YY) is —COR′, —CO₂R′, —CON(R′)₂, —SOR′,—SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or—PO(R′).

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, andthe other R^(XX) is C₁-C₆ alkyl.

In yet another embodiment, p₁ is 0, R^(YY) is hydrogen, one R^(XX) ishydrogen, and the other R^(XX) is C₁-C₆ alkyl.

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, andthe other R^(XX) is C₁-C₆ alkyl.

In yet another embodiment, p₁ is 0, R^(YY) is hydrogen, one R^(XX) ishydrogen, and the other R^(XX) is C₁-C₆ alkyl.

In one embodiment of the present invention, R¹ and R² together form aring as shown below:

In one embodiment, R^(XX) is C₁-C₆ alkyl.

In one embodiment, R^(XX) is methyl, n-propyl, isopropyl, n-butyl,isobutyl, or t-butyl.

In one embodiment, R¹ and R² taken together form ring (kk) as shownbelow:

G₃ is —N—, or CH;

each of m₂ and n₂ is independently 0-3, provided that m₂+n₂ is 2-6;p₂ is 0-2; provided that when G₃ is N, then p₂ is not 0;q₂ is 0 or 1;z is 0-4;Sp is a bond or a C₁-C₆ alkylidene linker, wherein up to two methyleneunits are optionally and independently replaced by —O—, —S—, —CO—, —CS—,—COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—, —NR′CO₂—, —NR′CONR′—,—OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —SO, —SO₂—, —NR′—, —SO₂NR′—,NR′SO₂—, or —NR′SO₂NR′—;ring B is a 4-8 membered, saturated, partially unsaturated, or aromatic,monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S,or N, wherein ring B is optionally substituted with w₂ independentoccurrences of —R¹², wherein w₂ is 0-4;

each occurrence of R¹² is independently Q-Rx; wherein Q is a bond or isa C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene unitsof Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—,—CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—,—CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—,—PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independentlyselected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic grouphaving up to three substituents; and each occurrence of R isindependently hydrogen or C₁₋₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ has up to foursubstituents; or R and R′, two occurrences of R, or two occurrences ofR′, are taken together with the atom(s) to which they are bound to forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, G₃ is N. Or, G₃ is CH.

In one embodiment, p₂ is 0. Or, p₂ is 1. Or, p₂ is 2.

In another embodiment, q₂ is 0. Or, q₂ is 1.

In one embodiment, p₂ is 1, and q₂ is 1.

In another embodiment, G₃ is CH, p₂ is 0, and q₂ is 1.

In one embodiment, m₂ and n₂ each is 1. Or, m₂ and n₂ each is 2.

In another embodiment, Sp is selected from —O—, —S—, or —NR′—. In oneembodiment, Sp is —O—. Or, Sp is —NR′—. Or, Sp is —NH—.

In one embodiment, ring B is a 4-8 membered, saturated, partiallyunsaturated, or aromatic, monocyclic heterocyclic ring having 1-4heteroatoms selected from O, S, or N, wherein ring B is optionallysubstituted with w₂ independent occurrences of —R¹² wherein w₂ is 0-4.

In another embodiment, ring B is a 4-8 membered, saturated, monocyclicheterocyclic ring having 1-4 heteroatoms selected from O, S, or N,wherein ring B is optionally substituted with w₂ independent occurrencesof —R¹², wherein w₂ is 0-4.

In yet another embodiment, ring B is a 5-6 membered, saturated,monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S,or N, wherein ring B is optionally substituted with w₂ independentoccurrences of —R¹², wherein w₂ is 0-4.

In one embodiment, w₂ is 0.

In another embodiment, ring B is tetrahydrofuranyl.

In yet another embodiment,

i) Sp is a bond, 0, or —CH₂—;ii) p₂ is 1;iii) R is hydrogen; andiv) n₂ and m₂ are both simultaneously 1 or 2.

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In one embodiment, R¹ and R² taken together form a ring of formula(kk-i) or formula (kk-ii):

According to one embodiment, ring B is a 5-6 membered, saturated,monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S,or N, wherein ring B is optionally substituted with w₂ independentoccurrences of —R², wherein w₂ is 0-4.

According to another embodiment, R is hydrogen. Or, R is hydrogen andring B is tetrahydrofuranyl.

According to yet another embodiment, Sp is a bond, —O—, or —O—CH₂—.

In one embodiment, R¹ and R² taken together form a ring (11):

each of m₃ and n₃ is independently 0-3, provided that m₃+n₃ is 2-6;z is 0-4;Sp is —O—, —S—, —NR′—, or a C₁-C₆ alkylidene linker, wherein up to twomethylene units are optionally and independently replaced by —O—, —S—,—CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—, —NR′CO₂—,—NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —SO, —SO₂—, —NR′—,—SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—, provided that Sp³ is attached to thecarbonyl group through an atom other than carbon; ring B₃ is a 4-8membered, saturated, partially unsaturated, or aromatic, monocyclicheterocyclic ring having 1-4 heteroatoms selected from O, S, or N,wherein ring B₃ is optionally substituted with w₃ independentoccurrences of —R¹³, wherein w₃ is 0-4;

each occurrence of R¹³ is independently Q-R^(X); wherein Q is a bond oris a C₁-C₆ alkylidene chain wherein up to two non-adjacent methyleneunits of Q are optionally and independently replaced by —NR—, —S—, —O—,—CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—,—NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—,—PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx isindependently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′S₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic grouphaving up to three substituents; and each occurrence of R isindependently hydrogen or C₁₋₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ has up to foursubstituents; or R and R′, two occurrences of R, or two occurrences ofR′, are taken together with the atom(s) to which they are bound to forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, Sp³ is selected from —O—, —S—, or —NR′—. Or, Sp is—O—. Or, Sp³ is —O—CH₂—. In another embodiment, Sp³ is —NR′—. Or, Sp³ is—NH—. Or, Sp³ is —NH—CH₂—.

In one embodiment, each of m₃ and n₃ is 1. In another embodiment, eachof m₃ and n₃ is 2.

In one embodiment, ring B₃ is a 4-8 membered, saturated, partiallyunsaturated, or aromatic, monocyclic heterocyclic ring having 1-4heteroatoms selected from O, S, or N, wherein ring B₃ is optionallysubstituted with w₃ independent occurrences of —R¹³, wherein w₃ is 0-4.

In another embodiment, ring B₃ is a 4-8 membered, saturated, monocyclicheterocyclic ring having 1-4 heteroatoms selected from O, S, or N,wherein ring B₃ is optionally substituted with w₃ independentoccurrences of —R³, wherein w₃ is 0-4.

In yet another embodiment, ring B₃ is a 5-6 membered, saturated,monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S,or N, wherein ring B₃ is optionally substituted with w₃ independentoccurrences of —R³, wherein w₃ is 0-4.

In one embodiment, w₃ is 0.

In another embodiment, ring B₃ is tetrahydrofuranyl.

In yet another embodiment, Sp³ is a bond, 0, or —O—CH₂—; R is hydrogen;and n₃ and m₃ are both simultaneously 1 or 2.

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In another embodiment, z is 0.

According to one embodiment, ring B₃ is a 5-6 membered, saturated,monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S,or N, wherein ring B₃ is optionally substituted with w₃ independentoccurrences of —R³, wherein w₃ is 0-4.

According to another embodiment, R is hydrogen. Or, R is hydrogen andring B₃ is tetrahydrofuranyl.

According to yet another embodiment, Sp₃ is a bond, —O—, —O—CH₂—, or—NH—CH₂.

In one embodiment, R¹ and R² taken together form a ring (mm):

each of m₄ and n₄ is independently 0-3, provided that m₄+n₄ is 2-6;p₄ is 1-2;R^(YZ) is C₁-C₆ aliphatic group, optionally substituted with w₄independent occurrences of —R¹⁴, wherein w₄ is 0-3;

each occurrence of R¹⁴ is independently Q-Rx; wherein Q is a bond or isa C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene unitsof Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—,—CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—,—CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—,—PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independentlyselected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic grouphaving up to three substituents; and each occurrence of R isindependently hydrogen or C₁₋₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ has up to foursubstituents; or R and R′, two occurrences of R, or two occurrences ofR′, are taken together with the atom(s) to which they are bound to forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, p₄ is 1. Or, p₄ is 2.

In one embodiment, m₄ and n₄ each is 1. Or, m₄ and n₄ each is 2. Or, m₄and n₄ each is 3.

In one embodiment, R^(YZ) is C₁-C₆ alkyl, optionally substituted with w₄independent occurrences of —R¹⁴, wherein w₄ is 0-3. In anotherembodiment, R^(YZ) is C₁-C₄ alkyl group optionally substituted with w₄independent occurrences of —R¹⁴, wherein w₄ is 0-3. Or, R^(Y) is C₁-C₆alkyl group.

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred Rgroups include methyl, ethyl, propyl, or butyl.

In another embodiment, R¹ and R² taken together form a ring (mm-1):

each of m₄ and n₄ is independently 0-3, provided that m₄+n₄ is 2-6;p₄ is 0-2;R^(YZ) is C₁-C₆ aliphatic group, optionally substituted with w₄independent occurrences of —R¹⁴, wherein w₄ is 0-3;

wherein up to two methylene units in R^(YZ) are optionally replaced with—NR—, —O—, —CO₂—, —OCO—, —NRCO—, —CONR—, —CO—, —SO₂NR—, or —NRSO₂—;

each occurrence of R¹⁴ is independently Q-R^(X); wherein Q is a bond oris a C₁-C₆ alkylidene chain wherein up to two non-adjacent methyleneunits of Q are optionally and independently replaced by —NR—, —S—, —O—,—CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—,—NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—,—PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx isindependently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′,—SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic grouphaving up to three substituents; and each occurrence of R′ isindependently hydrogen or C₁₋₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ has up to foursubstituents; or R and R′, two occurrences of R, or two occurrences ofR′, are taken together with the atom(s) to which they are bound to forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, p₄ is 1. Or, p₄ is 2.

In another embodiment, p₄ is 0.

In one embodiment, m₄ and n₄ each is 1. Or, m₄ and n₄ each is 2. Or, m₄and n₄ each is 3.

In one embodiment, R^(YZ) is C₁-C₆ alkyl, optionally substituted with w₄independent occurrences of —R¹⁴, wherein w₄ is 0-3. In anotherembodiment, R^(YZ) is C₁-C₄ alkyl group optionally substituted with w₄independent occurrences of —R⁴, wherein w₄ is 0-3. Or, R^(Y) is C₁-C₆alkyl group.

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred Rgroups include methyl, ethyl, propyl, or butyl.

In another embodiment, the present invention provides a compound offormula mm-2 or mm-3:

In one embodiment of formula mm-2 and mm-3, R^(YZ) is an unsubstitutedC₁-C₆ aliphatic group.

In one embodiment of formula mm-2, R^(YZ) is —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₃, —CH(CH₃)₃, —CH₂CH(CH₃)₂, or —CH₂C(CH₃)₃.

In one embodiment of formula mm-3, R^(YZ) is —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₃, —CH₂CH(CH₃)₂, or —CH₂C(CH₃)₃.

In one embodiment, R¹ and R² are taken together to form a ring (nn):

In one embodiment, G₁ is —N—. Or, G₁ is —CH—NH—. Or, G₁ is —CH—CH₂—NH—.

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, andthe other R^(XX) is C₁-C₆ alkyl.

In yet another embodiment, p₄ is 0, R^(YY) is hydrogen, one R^(XX) ishydrogen, and the other R^(XX) is C₁-C₆ alkyl.

In one embodiment, R¹ and R² are taken together to form a ring (pp):

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, andthe other R^(XX) is C1-C6 alkyl.

In yet another embodiment, p₄ is 0, R^(YY) is hydrogen, one R^(XX) ishydrogen, and the other R^(XX) is C1-C6 alkyl.

In one embodiment of the present invention, W is OR′. In anotherembodiment, W is OH.

In one embodiment of the present invention, W is SR′. In anotherembodiment, W is SH.

In one embodiment of the present invention, W is N(R′)₂. In anotherembodiment, W is NHR′. Or, W is NH₂.

In one embodiment of the present invention, W is CHF₂, or CH₂F. In oneembodiment, W is CHF₂. In another embodiment, W is CH₂F.

In another embodiment, W is CF₃.

In one embodiment of the present invention, z is 0-5. In anotherembodiment, z is 1-3. In yet another embodiment, z is 1-2. In yetanother embodiment, z is 1.

In one embodiment of the present invention, R⁴ is independently halogen,CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′,—NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, oran optionally substituted group selected from C₁-C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In another embodiment of the present invention, R⁴ is independently Cl,Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl.

In one embodiment of the present invention, R¹ and R², taken together isoptionally substituted azetidin-1-yl (aa), wherein z is 1 or 2 and atleast one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In anotherembodiment, R¹ and R², taken together is optionally substitutedazetidin-1-yl (aa), wherein z is 1 and R⁴ is —NRSO₂R′. In anotherembodiment, R¹ and R², taken together is optionally substitutedazetidin-1-yl (aa), wherein z is 1 and R⁴ is —NRCOOR′. In anotherembodiment, R¹ and R², taken together is optionally substitutedazetidin-1-yl (aa), wherein z is 1 and R⁴ is —NRCOR′.

In yet another embodiment, R¹ and R², taken together is optionallysubstituted pyrrolidin-1-yl (bb), wherein z is 1 or 2 and R⁴ is Cl, Br,F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′.

In another embodiment, R¹ and R², taken together is optionallysubstituted piperidin-1-yl (cc), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′,—NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In another embodiment, R¹ and R²,taken together is optionally substituted piperidin-1-yl (cc), wherein zis 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In anotherembodiment, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (cc), wherein z is 1 and R⁴ is —NRSO₂R′. In anotherembodiment, R¹ and R², taken together is optionally substitutedpiperidin-1-yl (cc), wherein z is 1 and R⁴ is —NRCOOR′.

In yet another embodiment, R¹ and R², taken together is optionallysubstituted piperazin-1-yl (dd), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. Inanother embodiment, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (dd), wherein z is 1 and R⁴ is —SOR′. In anotherembodiment, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (dd), wherein z is 1 and R⁴ is —COOR′. In anotherembodiment, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (dd), wherein z is 1 and R⁴ is —CON(R′)₂. In anotherembodiment, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (dd), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In anotherembodiment, R¹ and R², taken together is optionally substitutedpiperazin-1-yl (dd), wherein z is 1 and R⁴ is —COR′.

In yet another embodiment, R¹ and R², taken together is optionallysubstituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂,—SO₂N(R′)₂, —COR′, or —COOR′. In another embodiment, R¹ and R², takentogether is optionally substituted morpholin-1-yl (ee) orthiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —SOR′. In anotherembodiment, R¹ and R², taken together is optionally substitutedmorpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is—COOR′. In another embodiment, R¹ and R², taken together is optionallysubstituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is1 and R⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken togetheris optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl(ff), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In another embodiment, R¹ andR², taken together is optionally substituted morpholin-1-yl (ee) orthiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —COR′.

In yet another embodiment, R¹ and R², taken together is optionallysubstituted azepan-1-yl (gg), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. Inanother embodiment, R¹ and R², taken together is optionally substitutedazepan-1-yl (gg), wherein z is 1 and R⁴ is —SOR′. In another embodiment,R¹ and R², taken together is optionally substituted azepan-1-yl (gg),wherein z is 1 and R⁴ is —COOR′. In another embodiment, R¹ and R², takentogether is optionally substituted azepan-1-yl (gg), wherein z is 1 andR⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken together isoptionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is—SO₂N(R′)₂. In another embodiment, R¹ and R², taken together isoptionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is —COR′.

In yet another embodiment, R¹ and R², taken together is optionallysubstituted azocan-1-yl (hh), wherein z is 1 or 2 and at least oneoccurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. Inanother embodiment, R¹ and R², taken together is optionally substitutedazocan-1-yl (hh), wherein z is 1 and R⁴ is —SOR′. In another embodiment,R¹ and R², taken together is optionally substituted azocan-1-yl (hh),wherein z is 1 and R⁴ is —COOR′. In another embodiment, R¹ and R², takentogether is optionally substituted azocan-1-yl (hh), wherein z is 1 andR⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken together isoptionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is—SO₂N(R′)₂. In another embodiment, R¹ and R², taken together isoptionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is —COR′.

In one embodiment, R³ is hydrogen. In one embodiment, R³ isindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′,—SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected fromC₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet another embodiment, each occurrence of R³ is independently Cl,Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from piperidinyl, piperizinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In another embodiment, each occurrence of R³ is independently halogen,CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN.

In another embodiment, R³ is independently selected —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R³ is independently selected from —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In another embodiment, R³ is —CON(R′)₂, or —NRCOR′.

In one embodiment, y is 0-5. In another embodiment, y is 0. Or, y is1-3. In another embodiment, y is 1-2. Or, y is 1.

In one embodiment, R⁵ is independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁-C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In another embodiment, R⁵ is independently Cl, Br, F, CF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂,—OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl,OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy,or optionally substituted benzyloxy.

In another embodiment, R⁵ is F. Or, R⁵ is OR′. In one embodiment, R⁵ isOH.

In one embodiment, the present invention provides a compound of formulaI-i-A, formula I-ii-A, or formula I-iii-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-iv-A, formula I-v-A, or formula I-vi-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-vii-A, formula I-viii-A, or formula I-ix-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-x-A, formula I-xi-A, or formula I-xii-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-xiii-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, y is 0.

In another embodiment, R³ is hydrogen.

In another embodiment, R³ is X-R^(Q) and X is a C₁-C₆ alkylidene. Inanother embodiment, X is a C₁-C₄ alkylidene. Or, X is —CH₂—.

In one embodiment, R^(Q) is independently selected from —R′, —OR′, —SR′,—N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂.

In another embodiment R^(Q) is R′.

In one embodiment, R³ is independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁-C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet another embodiment, each occurrence of R³ is independently Cl,Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃,—NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or anoptionally substituted group selected from piperidinyl, piperazinyl,morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In another embodiment, each occurrence of R³ is independently halogen,CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN.

In another embodiment, R³ is independently selected —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R³ is independently selected from —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In another embodiment, R³ is —CON(R′)₂, or —NRCOR′.

In one embodiment, the present invention provides a compound of formulaI-i-B, formula I-ii-B, or formula I-iii-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-iv-B, formula I-v-B, or formula I-vi-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-vii-B, formula I-viii-B, or formula I-ix-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-x-B, formula I-xi-B, or formula I-xii-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formulaI-xiii-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

Exemplary compounds of formula I are shown below in Table 1:

TABLE 1  1  2  3

 4  5  6

 7  8  9

10 11 12

13 14 15

16 17

4. General Synthetic Methodology:

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Exemplary synthetic routes areillustrated below for the preparation of the compounds of the presentinvention.

Compounds of formula I-i may be prepared as illustrated below in Scheme1.

Conditions: a) Br₂, MeOH; b) 1. Et₃N, DMF, heat

Compounds of formula I-i may also be prepared as illustrated below inScheme 1a.

Conditions: a) Br₂, MeOH; b) Et₃N, DMF, heat

Compounds of formula I-ii may be prepared as illustrated below in Scheme2.

Conditions: a) Et₃N, THF, heat

Compounds of formula I-ii may also be prepared as illustrated below inScheme 2a-1.

Conditions: a) Et₃N, THF, heat

Compounds of formula I-iii may be prepared as illustrated below inScheme 3.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides,DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′,THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides,DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′,THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For X═Cl, Br, orF, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; forX═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For X═Cl, Br, orF, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; forX═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For X═Cl, CCl₃, orimidazolyl, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N,DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides,DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′,THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc;H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides,DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′,THF or DMF, heat.

Compounds of formula I-iii may be prepared as illustrated below inScheme 3.

Conditions: a) Br₂, MeOH; b) Et₃N, DMF, heat, 10 h

Compounds of formula I-iii may also be prepared as illustrated below inScheme 3a.

Conditions: a) Br₂, MeOH; b) Et₃N, DMF, heat Compounds of formula I-ivmay be prepared as illustrated below in Scheme 4.

Conditions: a) HBTU, DIEA, DMF; b) NaOMe-MeOH-THF

Compounds of formula I-iv may be prepared as illustrated below in Scheme4a.

Conditions: a) HBTU, DIEA, DMF; b) NaOMe, MeOH, THF

Compounds of formula I-v may be prepared as illustrated below in Scheme5.

Conditions: a) PdCl₂(dppf), Na₂CO₃, Tol, 140° C.; b) HNR¹R², DMF heat

Compounds of formula I-v may also be prepared as illustrated below inScheme 5a.

Conditions: a) PdCl₂(dppf), Na₂CO₃, toluene, 140° C.; b) HNR¹R², DMF,heat.

Compounds of formula I-vi may be prepared as illustrated below in Scheme6.

Conditions: a) p-TsOH, CH₂Cl₂; b) Zn(Cu), CH₂I₂, THF, heat

Compounds of formula I-vi may also be prepared as illustrated below inScheme 6a.

Conditions: a) i. PCl₅, CH₂Cl₂; ii. NaSCN, acetone; b) i. HNR¹R²,acetone; ii. MeI; c) Zn(Cu), CH₂I₂, 12, THF, heat.

Compounds of formula I-vii may be prepared as illustrated below inScheme 7.

Conditions: a) Et₃N, Dioxane-Ethanol, heat

Compounds of formula I-vii may also be prepared as illustrated below inScheme 7a.

Conditions: a) Et₃N, dioxane, ethanol, heat

Compounds of formula I-viii may be prepared as illustrated below inScheme 8.

Conditions: a) NaOMe, methanol, heat

Compounds of formula I-viii may also be prepared as illustrated below inScheme 8a.

Conditions: a) HNR¹R², DMF; b) Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O

Compounds of formula I-ix may be prepared as illustrated below in Scheme9.

Conditions: a) Nitrosoguanidine, THF; b) 220° C.

Compounds of formula I-ix may be prepared as illustrated below in Scheme9a.

Conditions: a) NaOH, ethanol, H₂O, heat

Compounds of formula I-x may be prepared as illustrated below in Scheme10.

Conditions: a) NaH, THF, MeI, CS₂; b) NH₂OH, HNR¹R²

Compounds of formula I-xi may be prepared as illustrated below in Scheme11.

Conditions: a) H₂O₂, ethanol-H₂O, heat

Compounds of formula I-xi may also be prepared as illustrated below inScheme 11a.

Conditions: a) Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; b) HNR¹R², DMF

Compounds of formula I-xii may be prepared as illustrated below inScheme 12.

Conditions: a) NaOH, ethanol-H₂O, heat

Compounds of formula I-xii may also be prepared as illustrated below inScheme 12a.

Conditions: a) NaOH, H₂O; b) 220° C.

Compounds of formula I-xiii may be prepared as illustrated below inScheme 13.

Conditions: a) Et₃NR¹R²NH, DMF; b) Ethanol, 0° C.-25° C.

Compounds of formula I-xiii may also be prepared as illustrated below inScheme 13a.

Conditions: a) Et₃N, R¹R²NH, DMF; b) ethanol, 0° C.-25° C.

Compounds of formula I-i-A may be prepared as illustrated below inScheme A-1.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat; ii. deprotect

Compounds of formula I-ii-A may be prepared as illustrated below inScheme A-2.

Conditions: a) i. Et₃N, THF, heat; ii. deprotect

Compounds of formula I-ii-A may also be prepared as illustrated below inScheme A-2-1.

Conditions: a) i. Et₃N, THF, heat; ii. Deprotect.

Compounds of formula I-iii-A may be prepared as illustrated below inScheme A-3.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat, 10 h; ii. deprotect

Compounds of formula I-iii-A may also be prepared as illustrated belowin Scheme A-3-1.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat; ii. deprotect

Compounds of formula I-iv-A may be prepared as illustrated below inScheme A-4.

Conditions: a) HBTU, DIEA, DMF; b) i. NaOMe-MeOH-THF; ii. deprotect

Compounds of formula I-iv-A may also be prepared as illustrated below inScheme A-4-1.

Conditions: a) HBTU, DIEA, DMF; b) i. NaOMe, MeOH, THF; ii. deprotect

Compounds of formula I-v-A may be prepared as illustrated below inScheme A-5.

Conditions: a) PdCl₂(dppf), Na₂CO₃, Tol, 140° C.; b) i. HNR¹, R², DMFheat; ii. deprotect

Compounds of formula I-v-A may also be prepared as illustrated below inScheme A-5-1.

Compounds of formula I-vi-A may be prepared as illustrated below inScheme A-6.

Conditions: a) p-TsOH, CH₂Cl₂; b) i. Zn(Cu), CH₂I₂, THF, heat; ii.deprotect

Compounds of formula I-vi-A may also be prepared as illustrated below inScheme A-6-1.

Conditions: a) i. PCl₅, CH₂Cl₂; ii. NaSCN, acetone; b) i. HNR¹R²,acetone; ii. MeI; c) i. Zn(Cu), CH₂I₂, 12, THF, heat; ii. Deprotect.

Compounds of formula I-vii-A may be prepared as illustrated below inScheme A-7.

Conditions: a) i. Et₃N, Dioxane-Ethanol, heat; ii. deprotect

Compounds of formula I-viii-A may be prepared as illustrated below inScheme A-8.

Conditions: a) i. NaOMe, methanol, heat; ii. deprotect

Compounds of formula I-viii-A may also be prepared as illustrated belowin Scheme A-8-1.

Conditions: a) HNR¹R², DMF; b) i. Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; ii.deprotect

Compounds of formula I-ix-A may be prepared as illustrated below inScheme A-9.

Conditions: a) Nitrosoguanidine, THF; b) i. 220° C.; ii. deprotect

Compounds of formula I-ix-A may also be prepared as illustrated below inScheme A-9-1.

Conditions: a) i. NaOH, ethanol, H₂O, heat; ii. Deprotect.

Compounds of formula I-x-A may be prepared as illustrated below inScheme A-10.

Conditions: a) i. NaOH, methanol, heat; ii. deprotect

Compounds of formula I-x-A may also be prepared as illustrated below inScheme A-10-1.

Conditions: a) NaH, THF, MeI, CS₂; b) NH₂OH, HNR¹R²

Compounds of formula I-xi-A may be prepared as illustrated below inScheme A-11.

Conditions: a) i. H₂O₂, ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xi-A may also be prepared as illustrated below inScheme A-11-1.

Conditions: a) Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; b) i. HNR¹R², DMF; ii.deprotect.

Compounds of formula I-xii-A may be prepared as illustrated below inScheme A-12.

Conditions: a) i. NaOH ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xii-A may also be prepared as illustrated belowin Scheme A-12-1.

Conditions: a) NaOH, H₂O; b) i. 220° C.; ii. deprotect.

Compounds of formula I-xiii-A may be prepared as illustrated below inScheme A-13.

Conditions: a) Et₃N, R¹R²NH, DMF; b) i. Ethanol, 0° C.-25° C.; ii.deprotect

Compounds of formula I-xiii-A-1 may be prepared as illustrated below inScheme A-13-1.

Conditions: a) Et₃N, R¹R²NH, DMF; b) i. ethanol, 0° C.-25° C.; ii.deprotect

Compounds of formula I-1-B may be prepared as illustrated below inScheme B-1.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat; ii. deprotect

Compounds of formula I-ii-B may be prepared as illustrated below inScheme B-2.

Conditions: a) i. Et₃N, THF, heat; ii. deprotect

Compounds of formula I-iii-B may be prepared as illustrated below inScheme B-3.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat, 10 h; ii. deprotect

Compounds of formula I-iv-B may be prepared as illustrated below inScheme B-4.

Conditions: a) HBTU, DIEA, DMF; b) i. NaOMe-MeOH-THF; ii. deprotect

Compounds of formula I-v-B may be prepared as illustrated below inScheme B-5.

Conditions: a) PdCl₂(dppf), Na₂CO₃, Tol, 140° C.; b) i. HNR¹R², DMFheat; ii. deprotect

Compounds of formula I-v-B may also be prepared as illustrated below inScheme B-5-1.

Conditions: a) PdCl₂(dppf), Na₂CO₃, toluene, 140° C.; b) i. HNR¹R², DMFheat; ii. deprotect.

Compounds of formula I-vi-B may be prepared as illustrated below inScheme B-6.

Conditions: a) p-TsOH, CH₂Cl₂; b) i. Zn(Cu), CH₂I₂, THF, heat; ii.deprotect

Compounds of formula I-vi-B may also be prepared as illustrated below inScheme B-6-1.

Conditions: a) i. PCl₅, CH₂Cl₂; ii. NaSCN, acetone; b) i. HNR¹R²,acetone; ii. MeI; c) i. Zn(Cu), CH₂I₂, 12, THF, heat; ii. deprotect.

Compounds of formula I-vii-B may be prepared as illustrated below inScheme B-7.

Conditions: a) i. Et₃N, Dioxane-Ethanol, heat; ii. deprotect

Compounds of formula I-viii-B may be prepared as illustrated below inScheme B-8.

Conditions: a) i. NaOMe, methanol, heat; ii. deprotect

Compounds of formula I-viii-B may be prepared as illustrated below inScheme B-8-1.

Conditions: a) HNR¹R², DMF; b) i. Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; ii.deprotect.

Compounds of formula I-ix-B may be prepared as illustrated below inScheme B-9.

Conditions: a) Nitrosoguanidine, THF; b) i. 220° C.; ii. deprotect

Compounds of formula I-ix-B may also be prepared as illustrated below inScheme B-9-1.

Conditions: a) i. NaOH, ethanol, H₂O, heat; ii. deprotect

Compounds of formula I-x-B may be prepared as illustrated below inScheme B-10.

Conditions: a) i. NaOH, methanol, heat; ii. deprotect

Compounds of formula I-x-B may also be prepared as illustrated below inScheme B-10-1.

Compounds of formula I-xi-B may be prepared as illustrated below inScheme B-11.

Conditions: a) i. H₂O₂, ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xi-B may also be prepared as illustrated below inScheme B-11-1.

Compounds of formula I-xii-B may be prepared as illustrated below inScheme B-12.

Conditions: a) i. NaOH, ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xii-B may be prepared as illustrated below inScheme B-12-1.

Compounds of formula I-xiii-B may be prepared as illustrated below inScheme B-13.

Conditions: a) Et₃N, R¹R²NH, DMF; b) i. Ethanol, 0° C.-25° C.; ii.deprotect

Compounds of formula I-xiii-B-1 may be prepared as illustrated below inScheme B-13-1.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of voltage-gated sodium ion channels and/or calcium channels,and thus the present compounds are useful for the treatment of diseases,disorders, and conditions including, but not limited to acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, and incontinence.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel orcalcium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome,incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof. In certain embodiments, a method for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain is provided comprising administering an effectiveamount of a compound or a pharmaceutically acceptable composition to asubject in need thereof. In certain other embodiments, a method for thetreatment or lessening the severity of radicular pain, sciatica, backpain, head pain, or neck pain is provided comprising administering aneffective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In still other embodiments, amethod for the treatment or lessening the severity of severe orintractable pain, acute pain, postsurgical pain, back pain, tinnitis orcancer pain is provided comprising administering an effective amount ofa compound or a pharmaceutically acceptable composition to a subject inneed thereof.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “patient”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels or calcium channels,preferably N-type calcium channels. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of NaV1.1,NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, orCaV2.2, and thus, without wishing to be bound by any particular theory,the compounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2, is implicated in a particular disease, condition, ordisorder, the disease, condition, or disorder may also be referred to asa “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediatedcondition or disorder”. Accordingly, in another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity of oneor more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.8. In other embodiments, compounds of theinvention are useful as inhibitors of NaV1.8 and CaV2.2. In still otherembodiments, compounds of the invention are useful as inhibitors ofCaV2.2. In yet other embodiments, compounds of the invention are usefulas dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such asNaV1.3 or NaV1.7.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 activity in a biological sample or a patient, which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, the study of sodium ion channels in biological and pathologicalphenomena; and the comparative evaluation of new sodium ion channelinhibitors.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLE Benzyl4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (9)

A solution of benzyl 4-thiocarbamoylpiperazine-1-carboxylate (2.7 g, 9.7mmol), 2-bromo-1-(2-fluorophenyl)ethanone (2.1 g, 9.7 mmol), diisopropylethylamine (1.9 mL, 11 mmol), and THF (32 mL) was sealed in a microwavevessel and heated by microwave irradiation at 120° C. for 20 seconds.The reaction was cooled to room temperature, diluted with water, andextracted with CH₂Cl₂. The combined extracts were washed with water,dried over Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by flash chromatography (SiO₂, 0%-30% EtOAc/hexanes) togive benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate(1.05 g, 27% yield). LC/MS: m/z 398.3 (M+H)⁺ at 3.84 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

1-(4-(2-Fluorophenyl)thiazol-2-yl)piperazine

To a solution of benzyl4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (0.85 g, 2.1mmol) in CH₂Cl₂ (2 μL) cooled to −50° C. was added boron tribromide (1 Min CH₂Cl₂, 8.6 mL, 8.6 mmol). The reaction was stirred at −50° C. for 20min and then carefully quenched with saturated aqueous NaHCO₃. Themixture was extracted with CH₂Cl₂, and the combined extracts were washedwith water, dried over Na₂SO₄, and concentrated under reduced pressureto yield 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine. LC/MS: m/z 264.1(M+H)⁺ at 2.04 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (10)

A solution of 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine (0.13 g, 0.50mmol), triethylamine (0.10 mL, 0.75 mmol), and CH₂Cl₂ (1.7 mL) wascooled in an ice bath, and isobutyl chloroformate (0.10 mL, 0.75 mmol)was added. The reaction was stirred at 0° C. for 20 min, diluted withCH₂Cl₂, washed with water, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to yield isobutyl4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate. LC/MS: m/z364.1 (M+H)⁺ at 3.87 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate

A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (0.21 g, 1.1 mmol),isobutyl piperidin-4-ylcarbamate (0.23 g, 1.2 mmol), and DMF (2 mL) wassealed in a microwave vessel and heated by microwave irradiation at 100°C. for two minutes. The reaction was cooled to room temperature, dilutedwith water, and extracted with CH₂Cl₂. The combined extracts were washedwith water, dried over Na₂SO₄, and concentrated under reduced pressureto yield isobutyl1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z365.0 (M+H)⁺ at 3.20 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate(20)

A mixture of isobutyl1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate (0.38 g, 1.1mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (0.35 g,1.6 mmol), Pd(Ph₃)₄ (12 mg, 11 μmol), K₂CO₃ (0.29 g, 2.1 mmol), CH₃CN(3.0 mL), and H₂O (0.3 mL) was sealed in a microwave vessel and heatedby microwave irradiation at 175° C. for 15 minutes. The reaction wascooled to room temperature, diluted with water, and extracted withCH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to yieldisobutyl1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate.LC/MS: m/z 377.3 (M+H)⁺ at 3.77 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

3-Chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole

A mixture of 3,5-dichloro-1,2,4-thiadiazole (0.14 g, 0.93 mmol),2-methoxyphenylboronic acid (0.16 g, 1.0 mmol), Pd(PPh₃)₄ (11 mg, 9.3mmol), K₂CO₃ (0.26 g, 1.9 mmol), and CH₃CN (3 mL containing 10% H₂O) wassealed in a microwave vessel and heated by microwave irradiation at 100°C. for three minutes. The reaction was cooled to room temperature,diluted with water, and extracted with CH₂Cl₂. The combined extractswere washed with water, dried over Na₂SO₄, and concentrated underreduced pressure to yield3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole. LC/MS: m/z 227 (M+H)⁺ at3.45 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

1-(5-(2-Methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine

A mixture of 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole (0.21 g,0.93 mmol), piperazine (400 mg, 4.65 mmol), and DMF (3 mL) was sealed ina microwave vessel and heated by microwave irradiation at 150° C. for 5minutes. The reaction was cooled to room temperature, diluted withwater, and extracted with CH₂Cl₂. The combined extracts were washed withwater, dried over Na₂SO₄, and concentrated under reduced pressure toyield 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine. LC/MS:m/z 277.1 (M+H)⁺ at 2.19 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)).

Isobutyl4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate

To a mixture of 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine(80 mg, 0.29 mmol) and triethylamine (61 μL, 0.43 mmol) in CH₂Cl₂ (0.5mL) at 0° C. was added isobutyl chloroformate (59 mg, 0.43 mmol) inCH₂Cl₂ (0.5 mL). The reaction mixture was stirred at 0° C. for 1 h,diluted with water, and extracted with CH₂Cl₂. The combined extractswere washed with water, dried over Na₂SO₄, and concentrated underreduced pressure to yield isobutyl4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate.LC/MS: m/z 377.5 (M+H)⁺ at 3.81 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Isobutyl4-(5-(2-hydroxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate(21)

To isobutyl4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylatefrom above was added boron tribromide solution (1 M in CH₂Cl₂, 1.7 mL,1.7 mmol) at −30° C. The reaction mixture was stirred at −30° C. for 1 hand at room temperature for 3 h. To this mixture was added borontribromide (1 M in CH₂Cl₂, 1.4 mL, 1.4 mmol), and the reaction wasstirred for another hour. The reaction mixture was diluted withsaturated NaHCO₃ and extracted with CH₂Cl₂. The combined extracts werewashed with water, dried over Na₂SO₄, and concentrated under reducedpressure to give a residue which was filtered and purified by reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to yieldisobutyl4-(5-(2-hydroxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate.LC/MS: m/z 363.3 (M+H)⁺ at 3.52 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Representative analytical data is shown below in Table 2 for thecompounds of the present invention.

TABLE 2 LC-MS LC-RT Cmpd. No. M + 1 min 1 260.8 3.54 2 362.2 3.85 3376.3 3.29 4 382.2 3.65 5 360.2 2.98 6 348.3 3.66 7 376.5 3.22 8 364.33.23 9 398.3 3.84 10 364.1 3.87 11 378.2 4.19 12 378.2 3.34 13 366.03.36 14 362.3 2.89 15 391.1 3.23 16 377.3 3.77 17 363.3 3.52

Assays for Detecting and Measuring NaV Inhibition Properties of Compound

Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (eeGonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with ChemicalStimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

1) On the day of the assay, medium is aspirated and cells are washedtwice with 225 μL of Bath Solution #2 (BS#2).2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin stocksolution with 10% Pluronic 127 1:1 and then dissolving the mix in theappropriate volume of BS#2.3) After bath solution is removed from the 96-well plates, the cells areloaded with 80 μL of the CC2-DMPE solution. Plates are incubated in thedark for 30 minutes at room temperature.4) While the cells are being stained with coumarin, a 15 μL oxonolsolution in BS#2 is prepared. In addition to DiSBAC₂(3), this solutionshould contain 0.75 mM ABSC1 and 30 μL veratridine (prepared from 10 mMEtOH stock, Sigma #V-5754).5) After 30 minutes, CC2-DMPE is removed and the cells are washed twicewith 225 μL of BS#2. As before, the residual volume should be 40 μL.6) Upon removing the bath, the cells are loaded with 80 μL of theDiSBAC₂(3) solution, after which test compound, dissolved in DMSO, isadded to achieve the desired test concentration to each well from thedrug addition plate and mixed thoroughly. The volume in the well shouldbe roughly 121 μL. The cells are then incubated for 20-30 minutes.7) Once the incubation is complete, the cells are ready to be assayed onVIPR® with a sodium addback protocol. 120 μL of Bath solution #1 isadded to stimulate the NaV dependent depolarization. 200 μL tetracainewas used as an antagonist positive control for block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} )}{( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} )}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated. For the Na⁺ addback analysis time windows, baseline is 2-7sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound Solutions [mM]Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH 7.4with NaOHBath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4 withKOH (final K concentration ˜5 mM)CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at −20°C.DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at roomtemperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

C) VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method#2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #p₂₄₄₃), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO 10 mM CC2-DMPE (Aurora#00-100-008) in dry DMSO 200 mM ABSC1 in H₂O

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a10 μM final staining concentration. The cells are stained for 30 minutesin the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The requiredamount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixedwith 1 μL 10% pluronic for each mL of solution to be made and vortexedtogether. Then HBSS/HEPES is added to make up 2× solution. Finally, theABSC1 is added.

The 2× DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the 2×DiSBAC₂(3) w/ ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay buffer #1140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose,pH 7.40, 330 mOsmPluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSOOxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSOCoumarin stock (1000×): 10 mM CC2-DMPE in dry DMSOABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

1. Insert or use electrodes into each well to be assayed.2. Use the current-controlled amplifier to deliver stimulation wavepulses for 3 s. Two seconds of pre-stimulus recording are performed toobtain the un-stimulated intensities. Five seconds of post-stimulationrecording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{( {{intensity}_{460\mspace{14mu} {nm}} - {background}_{460\mspace{14mu} {nm}}} )}{( {{intensity}_{580\mspace{14mu} {nm}} - {background}_{580\mspace{14mu} {nm}}} )}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22o C) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH2PO4 (0.44), MgCl₂ (0.5), MgSO4 (0.41), NaHCO3 (4), Na2HPO4 (0.3),glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

CURRENT-CLAMP Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filledwith (in mM): 150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

The activity of selected compounds of the present invention against NaV1.8 channel is shown below in Table 3. In Table 3, the symbols have thefollowing meanings: “+++” means <10 μM; “++” means between 10 μM and 20μM; and “+” means >20 μM.

TABLE 3 Compound # IC₅₀ 1 ++ 2 + 3 ++ 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 +12 + 13 + 14 + 15 + 16 + 17 +

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond; X₁ and X₂ each is independently ═CR³—, ═N—,—O—, —S—, or —NR³—; X₃ is R³ or a lone pair of electrons; provided thatX₁, X₂, and N(X₃), taken together with the intervening carbon atoms forma 5-membered heteroaryl ring; W is halo, OR′, SR′, N(R′)₂, NRC(O)R′,S(O)₂N(R′)₂, OC(O)R′, OC(O)N(R′)₂, NR(S(O)₂R′, OP(O)(OR′)₂, OP(O)₂OR′,OP(O)(R′)₂, CHF₂, CH₂F, or CF₃; R¹ and R², taken together with thenitrogen atom, form a 3-12-membered monocyclic or bicyclic saturated,partially unsaturated, or fully unsaturated ring having 0-3 additionalheteroatoms independently selected from nitrogen, sulfur, or oxygen,wherein said ring is optionally substituted at one or more substitutablering atoms with z independent occurrences of —R⁴, wherein z is 0-5; y is0-5; each occurrence of R³, R⁴, and R⁵ is independently Q-Rx; wherein Qis a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacentmethylene units of Q are optionally and independently replaced by —NR—,—S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—,—SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—,—SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx isindependently selected from —R′, halogen, —NO₂, —CN, —OR′, —SR′,—N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′,—CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′,—NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂,—OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; each occurrence of R isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup; each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that: (i) when X₁ is S, X₂ is ═CH—, X³ is a lone pair ofelectrons, W, together with R⁵ and y is 2,4-difluorophenyl, then R¹ andR² taken together is not optionally substituted2,3-dihydro-1H-isoindol-1-one-2-yl; (ii) when X₁ is S, X₂ is ═CH—, X³ isa lone pair of electrons, W, together with R⁵ and y is2,4-dichlorophenyl, then R¹ and R² taken together is not optionallysubstituted 2,3-dihydro-1H-indol-1-yl or an optionally substitutedtetracyclic ring system; (iii) when X₁ is S, X₂ is ═CMe-, X³ is a lonepair of electrons, W, together with R⁵ and y is 2,4-dimethoxyphenyl,then R¹ and R² taken together is not an optionally substitutedpyrrol-1-yl ring fused to an optionally substituted pyridazine ring;(iv) when X₁ is S, X₂ is ═CR³—, and X³ is a lone pair of electrons, thenR¹ and R² taken together is not an optionally substituted pyrrol-1-yl;(v) when X₁ is ═N—, X² is 0, X³ is a lone pair of electrons, and W ishalo, then R¹ and R² taken together is not1,4-diazabicyclo[3.2.2]nonan-1-yl; (vi) when X₁ is S, X₂ is ═CH—, X³ isa lone pair of electrons, W, together with R⁵ and y is 2-chlorophenyl,then R¹ and R² taken together is not an optionally substitutedimidazol-1-yl; (vii) when X₁ is ═N—, X₂ is ═CH—, X₃ is H, y is 0, and Wis NHSO₂Ar′, wherein Ar′ is an optionally substituted phenyl, then R¹and R² taken together is not 2-butanamido-pyrrolidin-1-yl; (viii) whenX₁ is ═N—, X₂ is ═CH— or ═C(Cl)—, X₃ is H, and W is NHSO₂Ar′, whereinAr′ is an optionally substituted phenyl or NHC(O)R, wherein R is anoptionally substituted aliphatic, then R¹ and R² taken together is not3-[(dimethylamino)sulfonyl]amino-morpholin-4-yl or2-(methoxycarbonyl)amino-4,5-dichloro-1H-imidazol-1-yl; (ix) when X₁ isS, X₂ is ═CH—, X₃ is a lone pair of electrons, W is OH or OMe, then R¹and R² taken together is not 3,4-dihydro-2-(1H)-quinozolin-3-one-2-yl;(x) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, and W ishalo or OR′, then R¹ and R² taken together is not an optionallysubstituted 2-imino-thiazolidin-4-one-3-yl; (xi) when X₁ is S, X₂ is═CH—, and X₃ is a lone pair of electrons, then R¹ and R² taken togetheris not an optionally substituted azetidin-2-one-1-yl; (xii) when X₁ isS, X₂ is ═CR³—, X₃ is a lone pair of electrons, and W is OH or halo,then R¹ and R² taken together is not an optionally substituted3,4-dihydro-(3H)-quinazolin-4-one-3-yl; (xiii) when X₁ is S, X₂ is═CR³—, X₃ is a lone pair of electrons, and W is halo, OMe, or NHSO₂Ar′,wherein Ar′ is an optionally substituted phenyl, then R¹ and R² takentogether is not an optionally substituted ring selected fromthiazolidin-4-one-3-yl, 2,4-dioxo-imidazolin-1-yl,4,5-dihydro-5-oxo-(1H)-imidazol-1-yl, or azetidin-1-yl; (xiv) when X₁ isS, X₂ is ═CH—, X₃ is a lone pair of electrons, and W is halo, then R¹and R² taken together is not1,2,3,4-tetrahydro-(1H)-quinazolin-2,4-dioxo-3-yl; and (xv) when X₁ is═N—, X₂ is ═CR³—, X₃ is H, then R¹ and R² taken together is not3,5-dioxo-1,2,4-triazolidin-4-yl, 2,5-dioxo-pyrrolidin-1-yl, or2,5-dioxo-imidazolidin-1-yl. 2-4. (canceled)
 5. A compound according toclaim 1, wherein R¹ and R² taken together form a piperazinyl ring:

6-9. (canceled)
 10. A compound according to claim 1, wherein R¹ and R²taken together form a ring (ii) or (jj) as shown below:

wherein: G₁ is —N—, —CH—NH—, or —CH—CH₂—NH—; each of ml and n1 isindependently 0-3, provided that m₁+n₁ is 2-6; p₁ is 0-2; z is 0-4; eachR^(XX) is hydrogen, C₁₋₆ aliphatic group, a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein R^(XX) is optionally substitutedwith w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3; providedthat both R^(XX) are not simultaneously hydrogen; R^(YY) is hydrogen,—COR′, —CO₂R′, —CON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or —PO(R′); each occurrence of R¹¹is independently Q-Rx; wherein Q is a bond or is a C₁-C₆ alkylidenechain wherein up to two non-adjacent methylene units of Q are optionallyand independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—,—COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—,—OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or—POR—; and each occurrence of Rx is independently selected from —R′,halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′,—NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′,—COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,or —OPO(R′)₂; and each occurrence of R is independently hydrogen or C₁₋₆aliphatic group having up to three substituents; and each occurrence ofR′ is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ has up to foursubstituents; or R and R′, two occurrences of R, or two occurrences ofR′, are taken together with the atom(s) to which they are bound to forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.11-34. (canceled)
 35. The compound according to claim 1, wherein R¹ andR² together form a ring as shown below:


36. The compound according to claim 35, wherein R^(XX) is C₁-C₆ alkyl.37. The compound according to claim 36, wherein R^(XX) is methyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.
 38. The compoundaccording to claim 1, wherein R¹ and R² taken together form ring (kk) asshown below:

G3 is —N—, or CH; each of m₂ and n2 is independently 0-3, provided thatm₂+n₂ is 2-6; p₂ is 0-2; provided that when G₃ is N, then p₂ is not 0;q₂ is 0 or 1; z is 0-4; Sp is a bond or a C₁-C₆ alkylidene linker,wherein up to two methylene units are optionally and independentlyreplaced by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—,—OCO—, —NR′CO₂—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—,—SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—; ring B is a 4-8membered, saturated, partially unsaturated, or aromatic, monocyclicheterocyclic ring having 1-4 heteroatoms selected from O, S, or N,wherein ring B is optionally substituted with w independent occurrencesof —R², wherein w₂ is 0-4; each occurrence of R¹² is independently Q-Rx;wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to twonon-adjacent methylene units of Q are optionally and independentlyreplaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—,—NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—,—NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and eachoccurrence of Rx is independently selected from —R′, halogen, ═O, ═NR′,—NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′,—COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂,—NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂,—P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and eachoccurrence of R is independently hydrogen or C₁₋₆ aliphatic group havingup to three substituents; and each occurrence of R′ is independentlyhydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′,two occurrences of R, or two occurrences of R′, are taken together withthe atom(s) to which they are bound to form an optionally substituted3-12 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. 39-67. (canceled)
 68. Thecompound according to claim 1, wherein R¹ and R² taken together form aring (II):

wherein: each of m₃ and n₃ is independently 0-3, provided that m₃+n₃ is2-6; z is 0-4; Sp³ is —O—, —S—, —NR′—, or a C₁-C₆ alkylidene linker,wherein up to two methylene units are optionally and independentlyreplaced by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—,—OCO—, —NR′CO₂—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—,—SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—, provided that Spis attached to the carbonyl group through an atom other than carbon;ring B₃ is a 4-8 membered, saturated, partially unsaturated, oraromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selectedfrom O, S, or N, wherein ring B₃ is optionally substituted with windependent occurrences of —R³, wherein w₃ is 0-4; each occurrence ofR¹³ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆alkylidene chain wherein up to two non-adjacent methylene units of Q areoptionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—,—OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—,—CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—,—PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independentlyselected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or C₁₋₆ aliphatic group having up to three substituents; andeach occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group,a 3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein R′ has up to four substituents; or R and R′, two occurrences ofR, or two occurrences of R′, are taken together with the atom(s) towhich they are bound to form an optionally substituted 3-12 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. 69-87. (canceled)
 88. The compoundaccording to claim 1, wherein R¹ and R² taken together form a ring (mm):

wherein: each of m₄ and n4 is independently 0-3, provided that m₄+n₄ is2-6; p₄ is 1-2; R^(YZ) is C₁-C₆ aliphatic group, optionally substitutedwith w₄ independent occurrences of —R⁴, wherein w₄ is 0-3; eachoccurrence of R¹⁴ is independently Q-R^(X); wherein Q is a bond or is aC₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units ofQ are optionally and independently replaced by —NR—, —S—, —O—, —CS—,—CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—,—CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—,—PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independentlyselected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂,—NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂,—OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂,—COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, or —OPO(R′)₂; and each occurrence of R is independentlyhydrogen or C₁₋₆ aliphatic group having up to three substituents; andeach occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group,a 3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein R′ has up to four substituents; or R and R′, two occurrences ofR, or two occurrences of R′, are taken together with the atom(s) towhich they are bound to form an optionally substituted 3-12 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. 89-99. (canceled)
 100. The compoundaccording to claim 1, wherein R¹ and R² are taken together to form aring (nn):

101-105. (canceled)
 106. The compound according to claim 1, wherein R¹and R² are taken together to form a ring (pp):

107-108. (canceled)
 109. The compound according to claim 1, wherein W isOR′.
 110. The compound according to claim 109, wherein W is OH. 111-115.(canceled)
 116. The compound according to claim 1, wherein W is CHF₂, orCH₂F. 117-183. (canceled)
 184. The compound according to claim 1,wherein X₁, X₂, and X₃ taken together form a ring selected from:


185. The compound according to claim 1, wherein X₁, X₂, and X₃ takentogether form a ring selected from:

186-189. (canceled)
 190. A compound according to claim 1, wherein saidcompound is selected from Table
 1. 191. A pharmaceutical compositioncomprising a compound according to claim 1 and a pharmaceuticallyacceptable adjuvant or carrier.
 192. A method for treating or lesseningthe severity of a disease, disorder, or condition selected from acute,chronic, neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain, said method comprising the step of administeringto said patient an effective amount of a composition according to claim191.
 193. The method according to claim 191, wherein the disease,condition, or disorder is implicated in the activation or hyperactivityof voltage-gated sodium channels. 194-197. (canceled)